Pyrrole derivatives, their preparation and their therapeutic application

ABSTRACT

The subject of the invention is compounds of formula (I): 
     
       
         
         
             
             
         
       
     
     in which R 1 -R 10  are as defined within, the method of preparation and therapeutic application as cannabinoid CB1 receptor antagonists.

The present invention relates to 1,5-diphenylpyrrole-3-carboxamide derivatives, to their preparation and to their therapeutic application.

Derivatives of 1,5-diphenylpyrrole-3-carboxamide, which are active as anti-obesity agents, have been described in patent application WO 2003/027 069. Derivatives of 1,5-diphenylpyrrole-3-carboxamide, exhibiting affinity for the CB₁ cannabinoid receptors, have been described in patent applications WO 2004/058 249 and WO 2005/080 328. Application WO 2006/024 777 claims 4,5-diphenylpyrrole-2-carboxamides exhibiting affinity for the CB₁ cannabinoid receptors.

Novel 1,5-diphenylpyrrole-3-carboxamide derivatives carrying a particular substituent at the 2-position of the pyrrole have now been found which possess antagonist properties for the CB₁ cannabinoid receptors. In particular, these novel derivatives have antagonist properties for the peripheral CB₁ receptors and exhibit low penetration at the level of the brain.

The subject of the present invention is compounds corresponding to the formula:

in which:

-   -   A represents a (C₁-C₆)alkylene group which is unsubstituted or         substituted one or more times with a (C₁-C₃)alkyl group or a         fluorine atom;     -   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group which is         unsubstituted or substituted with one or more fluorine atoms;     -   R₂ represents:         -   either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl             or azetidin-1-yl radical, the said radicals being             unsubstituted or substituted once or twice with a             substituent each independently chosen from a fluorine atom,             a group (C₁-C₄)alkoxyl, (C₁-C₄)alkyl, trifluoromethyl,             —OCF₃, —CH₂OH, —CONH₂ and/or a phenyl group, the said phenyl             group being unsubstituted or substituted once or twice with             a substituent each independently chosen from a halogen atom,             a —CF₃ group, a methoxyl group and/or a trifluoromethoxyl             group;         -   or an amino(C₁-C₆)alkyl group which is unsubstituted or             substituted with one or several substituents each             independently chosen from a fluorine atom, a hydroxyl group,             a —CONH₂ group and/or a phenyl group, the said phenyl group             being unsubstituted or substituted once or twice with a             substituent each independently chosen from a halogen atom, a             —CF₃ group, a methoxyl group and/or a trifluoromethoxyl             group;     -   or R₁ and R₂ together with the nitrogen atom to which they are         attached constitute:         -   either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the             said radicals being unsubstituted or substituted with a             phenyl, benzodioxolyl, benzodioxolylmethyl,             tetrahydrofuranylcarbonyl, —COR₁₁, and/or —CH₂COR₁₁ group;             the phenyl group being itself unsubstituted or substituted             once or several times with a substituent each independently             chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl,             hydroxyl, (C₁-C₄)alkoxyl and/or cyano group;         -   or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or             azetidin-1-yl radical, the said radicals being unsubstituted             or substituted once or twice with a substituent each             independently chosen from:         -   a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃,             —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; and/or —SO₂ NR₁₂R₁₃;         -   and/or a (C₁-C₄)alkyl group which is unsubstituted or             substituted with one or more substituents each independently             chosen from a halogen atom and/or a hydroxyl,         -   and/or a phenyl or pyridinyl group; the said groups being             unsubstituted or substituted once or several times with a             substituent each independently chosen from a halogen atom, a             (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl             and/or cyano group;         -   and/or a benzyl group which is unsubstituted or substituted             once or several times with a substituent each independently             chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl,             hydroxyl, (C₁-C₄)alkoxyl and/or cyano group;         -   and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl             group, the said groups being unsubstituted or substituted             once or several times with a substituent each independently             chosen from a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl,             hydroxyl, trifluoromethyl and/or —OCF₃ group;         -   and/or an aminophenyl or aminobenzyl group, the said groups             being unsubstituted or substituted once or several times             with a substituent each independently chosen from a halogen             atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl             and/or cyano group;         -   and/or an amino(C₃-C₇)cycloalkyl group which is             unsubstituted or substituted once or several times with a             substituent each independently chosen from a halogen atom, a             hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl and/or cyano group,             the said (C₁-C₄)alkyl group being unsubstituted or             substituted once or several times with a fluorine atom;     -   R₃, R₄, R₅, R₆, R₇, R₈ each independently represent a hydrogen         atom, a halogen atom, a —CN, —S(O)_(n)R₁₄ or —OS(O)_(n)R₁₄         group, or a (C₁-C₆)alkyl group which is unsubstituted or         substituted once or several times with a substituent each         independently chosen from a fluorine atom, an —OH, —OR₁₄,         —S(O)_(n)R₁₄, —OSO₂R₁₄ and/or —NHSO₂R₁₄ group, or a         (C₁-C₆)alkoxyl group, which is unsubstituted or substituted with         one or more substituents each independently chosen from a         fluorine atom, an —OH, —OR₁₄, —S(O)_(n)R₁₄, —OSO₂R₁₄ and/or         —NHSO₂R₁₄ group;     -   R₉ represents an —OR₁₂, —CN, —CO₂H, NR₁₂R₁₃, —CONR₁₂R₁₃, —NR₁         COR₁₂, —CONHNH₂, —CONHOH, —CONHSO₂R₁₄, —S(O)_(n)R₁₄,         —SO₂NR₁₂R₁₃, —NR₁₈SO₂R₁₄ or —NR₁₅SO₂NR₁₂R₁₃ group, or an         aromatic heterocycle chosen from:

-   -   R₁₀ represents a hydrogen or a (C₁-C₄)alkyl group;     -   R₁₁ represents:         -   a (C₁-C₄)alkyl, phenyl, benzyl, (C₁-C₄)alkoxyl, or             (C₁-C₃)alkylene-O—(C₁-C₃)alkyl group, the said groups being             unsubstituted or substituted with one or more substituents             each independently chosen from a (C₁-C₄)alkoxyl group, a             hydroxyl group and/or a fluorine atom;         -   a trifluoromethyl;         -   and/or an NR₁₆R₁₇ group;     -   R₁₂ and R₁₃ each independently represent a hydrogen atom or a         (C₁-C₆)alkyl group optionally substituted with one or more         substituents each independently chosen from a halogen atom, a         (C₃-C₇)cycloalkyl, cyano, —OH and/or —OR₁₄ group;     -   or R₁₂ and R₁₃ together with the nitrogen atom to which they are         attached constitute a 4- to 7-membered heterocyclic radical         which may contain a second heteroatom chosen from a nitrogen,         oxygen or sulphur atom;     -   n represents 0, 1 or 2;     -   R₁₄ represents a (C₁-C₄)alkyl group which is unsubstituted or         substituted with one or more fluorine atoms;     -   R₁₅ represents a hydrogen atom or a (C₁-C₄)alkyl group;     -   R₁₆ and R₁₇ each independently represent:         -   a hydrogen atom;         -   and/or a benzyl group which is unsubstituted or substituted             once or several times with a substituent each independently             chosen from a halogen atom, a methyl, trifluoromethyl,             hydroxyl, (C₁-C₄)alkoxyl and/or cyano group;         -   and/or a (C₁-C₆)alkyl group which is optionally substituted             with one or more substituents each independently chosen from             a halogen atom, a (C₃-C₇)cycloalkyl, cyano —OH, and/or —OR₁₄             group;     -   R₁₈ represents a hydrogen atom or a (C₁-C₄)alkyl group which is         unsubstituted or substituted with one or more fluorine atoms;         in the form of bases (=correspond to the free forms of the         compounds) and the salts thereof which are pharmaceutically         acceptable or acceptable for the purification and/or isolation         of the said compounds of formula (I).

The compounds of formula (I) may contain one or more asymmetric carbon atoms. They can therefore exist in the form of enantiomers or diastereoisomers. These enantiomers, diastereoisomers and mixtures thereof, including the racemic mixtures, form part of the invention.

The compounds of formula (I) may exist in the form of bases (that is to say as they are in their free forms), of addition salts with acids or of addition salts with bases. These salts are advantageously prepared with pharmaceutically acceptable salts but the salts of other acids which are useful, for example, for the purification or isolation of the compounds of formula (I) also form part of the invention.

The expression (C₁-C₃)alkyl, (C₁-C₄)alkyl or (C₁-C₆)alkyl group is understood to mean respectively a linear or branched alkyl radical of one to three carbon atoms, of one to four carbon atoms or of one to six carbon atoms, such as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, sec-butyl, tert-butyl, pentyl, isopentyl, n-hexyl or isohexyl radical. The methyl group is preferred for a (C₁-C₃)alkyl, for a (C₁-C₄)alkyl and for a (C₁-C₆)alkyl.

The expression (C₁-C₃)alkylene or (C₁-C₆)alkylene group is understood to mean respectively a linear bivalent carbon radical of one to three carbon atoms or of one to six carbon atoms such as —(CH₂)—, —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅— and —(CH₂)₆.

The expression (C₁-C₄)alkoxyl is understood to mean an oxygen atom attached to a linear or branched carbon radical of one to four carbon atoms such as methoxyl, ethoxy, propoxy, isopropoxy, butoxy, sec-butoxy or tert-butoxy radical. The methoxyl group is preferred.

The expression halogen atom is understood to mean a fluorine, chlorine, bromine or iodine atom, the fluorine, chlorine or bromine atoms being preferred. The expression (C₃-C₇)cycloalkyl group is understood to mean a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl radical.

The expression amino-cycloalkyl group is understood to mean, for the cycloalkyl part, a cyclopropyl, cyclobutyl, cyclopentyl, cyclohexyl or cycloheptyl carbon radical.

The expression 4- to 7-membered saturated or unsaturated heterocyclic radical, containing or not containing a second heteroatom such as O, N or S, is understood to mean in particular radicals such as homopiperidin-1-yl, morpholin-4-yl, piperidin-1-yl, piperazin-1-yl, pyrrolidin-1-yl, azetidin-1-yl, the piperidin-1-yl and pyrrolidin-1-yl radicals being preferred.

According to a first variant of the invention, the compounds of formula (IA) are differentiated in which:

-   -   R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group which is         unsubstituted or substituted with one or more fluorine atoms;     -   R₂ represents:         -   either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl             or azetidin-1-yl radical, the said radicals being             substituted once or twice with a substituent each             independently chosen from a fluorine atom, a group             (C₁-C₄)alkoxyl, (C₁-C₄)alkyl, trifluoromethyl, —OCF₃,             —CH₂OH, —CONH₂ and/or a phenyl group, the said phenyl group             being unsubstituted or substituted once or twice with a             substituent each independently chosen from a halogen atom, a             —CF₃ group, a methoxyl group and/or a trifluoromethoxyl             group;         -   or an amino(C₁-C₆)alkyl group which is substituted with one             or several substituents each independently chosen from a             fluorine atom, a hydroxyl group, a —CONH₂ group and/or a             phenyl group, the said phenyl group being unsubstituted or             substituted once or twice with a substituent each             independently chosen from a halogen atom, a —CF₃ group, a             methoxyl group and/or a trifluoromethoxyl group;     -   the other substituents being as defined for the compounds of         formula (I).

According to this first variant (IA), preference is given to the compounds in which the radical R₂ represents a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being substituted once or twice with a substituent each independently chosen from a fluorine atom, a (C₁-C₄)alkoxyl, trifluoromethyl, —OCF₃, —CH₂OH or —CONH₂ group and/or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group and/or a trifluoromethoxyl group.

According to this first variant (IA), preference is given to the compounds in which R₁ represents a hydrogen atom.

According to a second variant of the invention, the compounds of formula (IB) are differentiated in which R₁ and R₂ together with the nitrogen atom to which they are attached constitute:

-   -   either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the said         radicals being substituted with a phenyl, benzodioxolyl,         benzodioxolylmethyl, tetrahydrofuranylcarbonyl, —COR₁₁, and/or         —CH₂COR₁₁ group; the phenyl group being itself substituted once         or several times with a substituent each independently chosen         from a halogen atom, a methyl, trifluoromethyl, hydroxyl,         (C₁-C₄)alkoxyl and/or cyano group;     -   or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or         azetidin-1-yl radical, the said radicals being substituted once         or twice with a substituent each independently chosen from:     -   a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃,         —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; and/or —SO₂ NR₁₂R₁₃;     -   and/or a (C₁-C₄)alkyl group which is unsubstituted or         substituted with one or more substituents each independently         chosen from a halogen atom and/or a hydroxyl,     -   and/or a phenyl or pyridinyl group; the said groups being         unsubstituted or substituted once or several times with a         substituent each independently chosen from a halogen atom, a         methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl and/or cyano         group;     -   and/or a benzyl group which is substituted once or several times         with a substituent each independently chosen from a halogen         atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl and/or         cyano group;     -   and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group,         the said groups being unsubstituted or substituted once or         several times with a substituent each independently chosen from         a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl, hydroxyl,         trifluoromethyl and/or —OCF₃ group;     -   and/or an aminophenyl or aminobenzyl group, the said groups         being unsubstituted or substituted once or several times with a         substituent each independently chosen from a halogen atom, a         methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl and/or cyano         group;     -   and/or an amino(C₃-C₇)cycloalkyl group which is unsubstituted or         substituted once or several times with a substituent each         independently chosen from a halogen atom, a hydroxyl,         (C₁-C₄)alkyl, (C₁-C₄)alkoxyl and/or cyano group, the said         (C₁-C₄)alkyl group being unsubstituted or substituted once or         several times with a fluorine atom;     -   the other substituents being as defined for the compounds of         formula (I).

According to this second variant, preference is given to the compounds in which:

-   -   R₁ and R₂ together with the nitrogen atom to which they are         attached constitute a homopiperidin-1-yl, piperidin-1-yl,         pyrrolidin-1-yl or azetidin-1-yl radical, the said radical being         substituted once or twice with a substituent each independently         chosen from:         -   a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃,             —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; and/or —SO₂ NR₁₂R₁₃;         -   and/or a (C₁-C₄)alkyl group which is unsubstituted or             substituted with one or more substituents each independently             chosen from a halogen atom and/or a hydroxyl,         -   and/or a phenyl or pyridinyl group; the said groups being             unsubstituted or substituted once or several times with a             substituent each independently chosen from a halogen atom, a             (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl             and/or cyano group;         -   and/or a benzyl group which is substituted once or several             times with a substituent each independently chosen from a             halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl,             (C₁-C₄)alkoxyl and cyano group;         -   and/or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl             group, the said groups being unsubstituted or substituted             once or several times with a substituent each independently             chosen from a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl,             hydroxyl, trifluoromethyl and/or —OCF₃ group;         -   and/or an aminophenyl or aminobenzyl group, the said groups             being unsubstituted or substituted once or several times             with a substituent each independently chosen from a halogen             atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl,             (C₁-C₄)alkoxyl and/or cyano group;         -   and/or an amino(C₃-C₇)cycloalkyl group which is             unsubstituted or substituted once or several times with a             substituent each independently chosen from a halogen atom, a             hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl and/or cyano group,             the said (C₁-C₄)alkyl group being unsubstituted or             substituted once or several times with a fluorine atom;     -   the other substituents being as defined for the compounds of         formula (I).

According to this second variant (IB), preference is given in particular to the compounds in which R₁ and R₂ together with the nitrogen atom to which they are attached constitute a piperidin-1-yl radical which is substituted once or twice with a substituent. The substituent(s) are each independently chosen from those indicated above for this second variant (IB).

For the 2 variants according to the invention, preference is given to the compounds in which:

-   -   A represents an unsubstituted (C₁-C₅) alkylene group;     -   R₉ represents an —OR₁₂, —NR₁₂R₁₃, —CONR₁₂R₁₃, —NR₁₅COR₁₂,         —CONHNH₂, —CONHOH, —S(O)_(n)R₁₄, —SO₂NR₁₂R₁₃, —NR₁₈SO₂R₁₄, or         —NR₁₅SO₂NR₁₂R₁₃ group;     -   the other substituents being as defined above for the compounds         of formula (I).

In particular, for R₉, preference is given to an —OR₁₂, —NR₁₂R₁₃, —CONR₁₂R₁₃,

—NR₁₅COR₁₂ or —NR₁₈SO₂R₁₄ group. As regards the −OR₁₂ and —NR₁₂R₁₃ groups, preference is given more particularly to R₁₂ and R₁₃ which are different from hydrogen.

According to the present invention, preference is given to the compounds in which R₁₀ represents a hydrogen.

Among the compounds according to the invention, mention may be made in particular of the compounds below, as they are and the salts thereof:

Chemical structure IUPAC name (ACDName)

1′-{(1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulfphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- {[(trifluoromethyl)sulfonyl]amino}- propyl)-1H-pyrrol-3-yl]carbonyl}- 1,4′-bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3-pyrrolidin-1- ylpropyl)-1H-pyrrol-3-yl]carbonyl}- 4-phenylpiperidine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

1′-({1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-[3-(2- hydroxyethoxy)propyl]-1H-pyrrol-3- yl}carbonyl)-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(hydroxymethyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-1,4′- bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4- phenylpiperidine-4-carboxamide

4-amino-1-{[1-(4-chlorophenyl)-5- (2,4-dichlorophenyl)-2-(4- hydroxybutyl)-1H-pyrrol-3- yl]carbonyl}piperidine-4- carboxamide-1,1,1-trifluorobutane (1:1)

1{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3,3,3- trifluoropropyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(4- fluorobenzyl)amino]piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(4- fluorobenzyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(4-hydroxybutyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3- fluorobenzyl)amino]piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(2-hydroxyethyl)- 1H-pyrrol-3-yl]carbonyl}-4-[(3- fluorobenzyl)amino]piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4,4- dimethyl-1,4′-bipiperidine-4′- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4,4-dimethyl-1,4′- bipiperidine-4′-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}piperidine- 4-carboxamide

4-(4-chlorophenyl)-1-{[1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4,4-difluoro-1,4′- bipiperidine-4′-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1′-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4,4- difluoro-1,4′-bipiperidine-4′- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-N-(2- hydroxyethyl)piperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(3-amino-3-oxopropyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(3-amino-3-oxopropyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-phenylpiperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(3,3- difluoropyrrolidin-1-yl)piperidine-4- carboxamide

1-{[2-(4-amino-4-oxobutyl)-5-(2- chlorophenyl)-1-(4-chlorophenyl)- 1H-pyrrol-3-yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4- [(cyclopropylmethyl)amino]pipe- ridine-4-carboxamide

N-{3-[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-3-{[4-(3- hydroxypropyl)piperidin-1- yl]carbonyl}-1H-pyrrol-2- yl]propyl}methanesulphonamide

3-[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-3-{[4-(3- hydroxypropyl)piperidin-1- yl]carbonyl}-1H-pyrrol-2-yl]propan- 1-ol

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-{3- [(methylsulphonyl)amino]propyl}- 1H-pyrrol-3-yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[1-(4-chlorophenyl)-5-(2,4- dichlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[2-(5-amino-5-oxopentyl)-1-(4- chlorophenyl)-5-(2,4- dichlorophenyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

1-{[5-(2-chloro-4-fluorophenyl)-1- (4-chlorophenyl)-2-(3- hydroxypropyl)-1H-pyrrol-3- yl]carbonyl}-4-(4- fluorophenyl)piperidine-4- carboxamide

Among the compounds listed above, preference is given to:

-   1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; -   1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(2-hydroxyethyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; -   1′-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4,4-difluoro-1,4′-bipiperidine-4′-carboxamide; -   4-(4-chlorophenyl)-1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxy     propyl)-1H-pyrrol-3-yl]carbonyl}piperidine-4-carboxamide;

and their salts.

The subject of the present invention is also a method for preparing the compounds according to the invention.

This method is characterized in that the acid of formula (II) or a functional derivative of this acid of formula

in which R₃, R₄, R₅, R₆, R₇, R₉, R₁₀ and A-R₉ are as defined for (I), is treated with an amine of formula HNR₁R₂ in which R₁ and R₂ are as defined for (I).

Optionally, the compound thus obtained is converted to one of its salts.

As a functional derivative of the acid (II), use may be made of the acid chloride, the anhydride, a mixed anhydride, a C₁-C₄ alkyl ester in which the alkyl is straight or branched, a benzyl ester, an activated ester, for example the p-nitrophenyl ester, or the free acid opportunely activated, for example, with N,N-dicyclohexylcarbodiimide or with benzotriazol-1-yloxotris(dimethylamino)phosphonium hexafluorophosphate (BOP) or benzotriazol-1-yloxotris(pyrrolidino)phosphonium hexafluorophosphate (PyBOP) or N—[N-(dimethylamino)-1-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium N-oxide]hexafluorophosphate (HBTU). These functional derivatives of the acid (II) correspond to the compounds (Ilbis).

Thus, in the method according to the invention, it is possible to cause the acid chloride, obtained by the reaction of thionyl chloride with the acid of formula (II), to react with an amine HNR₁R₂, in an inert solvent, such as a chlorinated solvent (dichloromethane, dichloroethane, chloroform for example), an ether (tetrahydrofuran, dioxane for example), or an amide (N,N-dimethylformamide for example) under an inert atmosphere, at a temperature between 0° C. and room temperature, in the presence of a tertiary amine such as triethylamine, N-methylmorpholine or pyridine.

One variant consists in preparing the mixed anhydride of the acid of formula (II) by reacting ethyl chloroformate with the acid of formula (II), in the presence of a base such as triethylamine, and to cause it to react with an amine HNR₁R₂, in a solvent such as dichloromethane, under an inert atmosphere, at room temperature, in the presence of a base such as triethylamine.

Alternatively, the compounds of formulae (I) may be prepared according to the procedure of scheme 1 below.

According to scheme 1, the acid of formula (IIa) or one of its functional derivatives in which Z represents a group which is a chemical precursor of the group A-R₉ is treated with an amine of formula HNR₁R₂ as defined above in order to obtain an amide of formula (Ia).

Next, the group Z of the compound of formula (Ia) thus obtained is converted to a group A-R₉ by a method known to a person skilled in the art in order to obtain the product of formula (I).

By way of examples, the compounds of formula (I) in which R₉ corresponds to NHSO₂Alk, may be synthesized from the derivatives (IIa) in which Z corresponds to A-OCH₂Ph by reacting with an amine HNR₁R₂, followed by debenzylation as described in step (d2) of scheme 2 below, and application of the reaction sequence described in scheme 4 below.

The compounds of formula (I) obtained by the various procedures may be subsequently separated from the reaction medium and purified according to conventional methods, for example by crystallization or chromatography.

The compounds of formula (II) and their precursors may be prepared according to scheme 2 below:

Step (a2) is a regioselective alkylation of methyl acetoacetate according to the procedure described in particular in JACS 96(4) 1974, page 1082 to 1087.

Step (b2) is an alkylation of compound (III) with a bromoacetophenone, in the presence of NaH.

Step (c2) is a cyclization of the diketone (III) with a substituted aniline (Paal-Knorr reaction). This cyclization is conventionally carried out in a solvent such as toluene under reflux in the presence of para-toluenesulphonic acid, or in acetic acid. It is also possible to carry out this cyclization with better yields in the presence of catalysts such as Montmorillonite K10 and in a microwave oven, as described in Adv. Synth. Catal. 2006, 348, 2191-2196.

Step (d2) is a benzyl ether deprotection which may be carried out for example with the aid of BBr₃ or BCl₃ in dichloromethane.

The alcohol (VI) obtained is then saponified, preferably with LiOH, at 70° C. in a methanol-water mixture.

The acid (II) thus obtained is treated with the amine HN—R₁R₂ to form the product (I) of the invention.

According to the various values of the group A, it is possible to use various methods, known to a person skilled in the art, to prepare the compounds of formula (II) and the compounds of formula (I) according to the invention.

In particular, when A corresponds to —CH₂—, the synthesis of the compound (III) is carried out by treating methyl 4-chloroacetoacetate with benzyl alcohol in the presence of NaH as described in scheme 3 below:

According to the various values of the R₉ group, it is possible to use various methods, known to a person skilled in the art, to prepare the compounds of formula (II) and the compounds of formula (I) according to the invention.

Thus, when a compound of formula (I) is prepared in which A-R₉ represents the group —(CH₂)₃NHSO₂Alk, it is possible to carry out the procedure as according to scheme 4 below:

In this method, the alcohol (VI) is converted to a compound with a mesylate group (VIII) which is then treated with the sulphonamide H₂NSO₂Alk in order to obtain the alkylsulphonamide derivative (IX).

One variant consists in carrying out the procedure according to scheme 5 below by converting the compound with the mesylate group (VIII) to an amine, and then treating the latter with a compound of the AlkSO₂Cl type in order to obtain the ester (IX). The conversion of the alcohol (VI) to an amine (XIV) may be carried out by various methods known to a person skilled in the art, such as for example the Mitsunobu method.

The remainder of the synthesis is carried out by saponifying the ester (IX) and by coupling the acid obtained with the appropriate amine, as described in the general scheme 2.

In the case where the group R₉ represents COOH, the synthesis may be carried out according to scheme 6 below by oxidizing the compound (VI) to an acid with the aid of an oxidizing agent such as CrO₃, the acid obtained being protected with a t-butyl ester group. The methyl ester of the compound (XI) is saponified in order to obtain the acid (XII), which is then coupled with the amine HNR₁R₂ in order to obtain the ester (XIII) which is finally deprotected to give the compound according to the invention (I).

It is also possible, where appropriate, to directly oxidize a compound of formula (I), R₉ being equal to OH, with chromium VI in order to obtain the desired acid. This acid may then be treated so as to obtain the R₉ groups whose definition is given in the general formula.

The amines of formula HNR₁R₂ are known or prepared by known methods, for example that described in J. Med. Chem.; 7; 1964; 619, 622.

The subject of the present invention is also the compounds of formula (II) and their functional derivatives (Ilbis), used for the preparation of the compounds of formula (I). Among these compounds of formula (II) and (Ilbis), those of formula (IIter) are differentiated in particular:

in which:

-   -   X represents a halogen atom, a hydroxyl, (C₁-C₄)alkoxyl or         benzyloxy group;     -   and A, R₃, R₄, R₅, R₆, R₇, R₃ and R₁₀ are as defined for the         compounds of formula (I).

More particularly, the subject of the present invention is the compounds of formula:

in which

-   -   X represents a halogen atom, a hydroxyl, (C₁-C₄)alkoxyl or         benzyloxy group;     -   A represents a group —(CH₂)₂—, —(CH₂)₃—, —(CH₂)₄—, —(CH₂)₅—;     -   and R₉ represents a group —OR₁₂, —NR₁₂R₁₃, —CONR₁₂R₁₃,         —NR₁₅COR₁₂         -   or         -   —NR₁₈SO₂R₁₄.

As regards the —OR₁₂ and —NR₁₂R₁₃ groups in the compounds of formula (IIter), preference is given more particularly to R₁₂ and R₁₃ which are different from hydrogen. More particularly, preference is given to R₉ which represents —OH, —NHSO₂CH₃, —NHSO₂CF₃, —O—(CH₂)₂—OH.

The following examples describe the preparation of some compounds in accordance with the invention. These examples are not limiting and merely illustrate the present invention. The numbers for the compounds exemplified refer to those given in the table below, which illustrates the chemical structures and the physical properties of some compounds according to the invention.

In the examples, the following abbreviations are used:

-   -   AcOEt: ethyl acetate     -   BCl₃: boron trichloride     -   DCM or CH₂Cl₂: dichloromethane     -   DIPEA: diisopropylethylamine     -   DMAP: dimethylaminopyridine     -   DMF: N,N-dimethylformamide.     -   HPLC: high-performance liquid chromatography     -   HBTU:         N—[N-(dimethylamino)-1-1,2,3-triazolo[4,5-b]pyridin-1-ylmethylene]-N-methylmethanaminium         N-oxide]hexafluorophosphate     -   HOBt: 1-hydroxybenzotriazole     -   NaHCO₃: sodium hydrogen carbonate     -   MeOH: methanol     -   PyBOP: benzotriazol-1-yloxotris(pyrrolidino)phosphonium     -   hexafluorophosphate     -   RT: room temperature     -   TBTU: 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetramethyluronium         tetrafluoroborate     -   THF: tetrahydrofuran     -   HPLC: ‘Ultra Performance’ liquid chromatography

The nuclear magnetic resonance spectra are recorded at 250 MHz or at 400 MHz in DMSO-d6. For the interpretation of the spectra, the following abbreviations are used:

s: singlet, t: triplet, u.c.: unresolved complex, bm: broad multiplet, mt: multiplet, bs: broad singlet, bd: broad doublet, d: doublet, dd: doublet of doublet, dt: doublet of triplet, bt: broad triplet, 2s: 2 singlet, q: quadruplet, quin: quintuplet.

The compounds according to the invention are analyzed by LC/UV/MS (liquid chromatography/UV detection/mass spectrometry) coupling. The characteristic molecular peak (MH⁺, MNa⁺, etc.) and the retention time (tr) in minutes (min) are measured.

Conditions A (HPLC)

Use is made of a Symmetry C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

-   -   solvent A: 0.005% of trifluoroacetic acid (TFA) in water at pH         3.1;     -   solvent B: 0.005% of TFA in acetonitrile.

Gradient:

Time (min) % A % B 0 100 0 10 10 90 15 10 90 16 100 0 20 100 0

Column temperature: 30° C., flow rate 0.4 ml/minute.

The UV detection is carried out at λ=210 nM and the mass detection in positive ESI chemical ionization mode.

The UV detection is carried out with a diode array detector between 210 and 400 nm and the mass detection in positive ESI mode.

Conditions B (HPLC)

Use is made of an Xterra MS C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

-   -   solvent A: 10 mM AcONH₄ at about pH 7     -   solvent B: acetonitrile

Gradient:

Time (min) % A % B 0 100 0 10 10 90 15 10 90 16 100 0 20 100 0

Column temperature: 30° C., flow rate: 0.4 ml/minute.

Detection: λ=220 nm

Conditions C (HPLC):

Use is made of an Acquity BEH C18 column (50×2.1 mm; 1.7 μm)

The eluent is made up as follows:

-   -   solvent A: 0.005% of TFA in water at about pH 3.1/acetonitrile         (97/3)     -   solvent B: 0.035% of TFA in acetonitrile

Gradient:

Time (min) % A % B 0 100 0 2.3 5 95 2.9 5 95 3 100 0 3.5 100 0

Column temperature: 40° C., flow rate: 1 ml/minute.

Detection: λ=220 nm

Conditions D

Use is made of an Xterra MS C18 column of 2.1×50 mm, 3.5 μm.

The eluent is made up as follows:

-   -   solvent A: 0.005% of TFA in water at about pH 3.1/acetonitrile         (97/3)

solvent B: acetonitrile

Gradient:

Time (min) % A % B 0 95 5 17 10 90 22 10 90

Column temperature: ambient, flow rate: 0.4 ml/minute.

Detection: λ=220 nm

Conditions E:

Use is made of an Acquity BEH C18 column of 2.1×50 mm; 1.7 μm)

The eluent is made up as follows:

-   -   solvent A: 0.05% of TFA in water at about pH 3.1/acetonitrile         (97/3)     -   solvent B: 0.035% of TFA in acetonitrile.

Gradient:

Time (min) % A % B 0 99 1 2.3 5 95 2.9 5 95 3 99 1 3.5 99 1

Column temperature: 40° C., flow rate: 1 ml/minute.

Detection: λ=220 nm

PREPARATIONS Preparation 1 5-(4-Chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methanesulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid 1A) Methyl ester of 6-benzyloxy-3-oxohexanoic acid (synthesis carried out based on: Angewandte Chemie (Int. Ed) 38(9), 1999, 1263-1266).

9.64 g of NaH are suspended in 300 ml of anhydrous THF. The suspension is cooled to 0° C. 20 g of methyl acetoacetate are added dropwise and the mixture is kept stirred for 45 minutes. The solution is then cooled to −20° C., and 96 ml of a 2.5 molar solution of n-BuLi in hexane are added. After stirring for 15 minutes, 51.8 g of benzyl 2-bromoethyl ether are added and the temperature is allowed to rise to 0° C. The solution is then neutralized with 200 ml of 1N HCl. The solution is diluted with 500 ml of ether, washed with H₂O, dried over MgSO₄, and evaporated. 50 g of an oil are obtained which, after chromatography (eluent cyclohexane/ethyl acetate), give 22.6 g of a colourless oil.

LCMS: M Na⁺=273, tr=8.18.

1B) Methyl ester of 6-benzyloxy 2-2[2-(2,4-dichlorophenyl)-2-oxoethyl]-3-oxo-hexanoic acid

3.61 g of NaH are suspended in 500 ml of anhydrous THF. The mixture is cooled to 0° C. and 22.6 g of the compound of the preceding step 1A) diluted in 200 ml of THF are added dropwise. The mixture is kept stirred for 30 minutes and 24.1 g of 2,4-dichlorophenyl bromomethyl ketone dissolved in 100 ml of THF are added dropwise. The mixture is kept stirred for 3 hours at 0° C., and then for 17 hours at RT. The suspension is cooled to 0° C., and neutralized with 200 ml of N HCl. The mixture is extracted with ether, washed with H₂O, dried over MgSO₄, evaporated and chromatographed on 400 g of silica (eluent: cyclohexane/EtOAc). 25.7 g of the target compound are obtained.

LCMS: M=436(2Cl), tr=11.01.

1C) Methyl ester of 2-(3-benzyloxypropyl)-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxylic acid

In a round-bottomed flask provided with a Dean-Stark condenser, 25.7 g of the compound obtained in the preceding step 1B) in 400 ml of toluene are heated under reflux for 3 days with 1 g of para-toluenesulphonic acid and 8.4 g of 4-chlorophenyl amine. The solution is then diluted with EtOAc, washed with saturated NaHCO₃, N HCl, dried over MgSO₄ and evaporated. The oil obtained is purified by chromatography on 400 g of silica (eluent cyclohexane/EtOAc gradient) to give 23.6 g of the desired compound.

LCMS: MNa⁺=524.8(3Cl) tr=9.95.

1D) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxypropyl)-1H-pyrrole-3-carboxylic acid

23.6 g of the compound obtained above in step 1C) are introduced into 300 ml of CH₂Cl₂. The mixture is cooled to −5° C. and a solution of 40 g of BCl₃ dimethyl sulphide in THF is added. The mixture is kept stirred for one hour, and then 70 ml of H₂O are added, the mixture is allowed to separate by settling, the organic phase is washed with H₂O, dried over MgSO₄, concentrated under vacuum and the product obtained is purified by chromatography on silica (eluent cyclohexane/EtOAc gradient). 15.6 g of the desired compound are obtained.

1E) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-methanesulphonyloxypropyl)-1H-pyrrole-3-carboxylic acid

0.5 g of the compound obtained in 1D) is introduced into 10 ml of CH₂Cl₂. 0.4 ml of DIPEA and 153 mg of DMAP are added. The mixture is cooled to −10° C. and 150 mg of mesyl chloride are added. The mixture is allowed to react for 2 hours at −10° C., washed with a solution of H₂O buffered to pH=2. The organic phase is dried over MgSO₄ and then evaporated. 0.59 g of the desired compound is obtained in the form of an oil.

LCMS: MH⁺=516.1, tr=2.06.

1F) Methyl ester of 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methane-sulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid

This step is carried out according to the information published in: Tetrahedron Letters 46 (2005) page 22159-2161.

18 mg of NaH are introduced into 10 ml of anhydrous DMF. The mixture is cooled to 0° C. and 42.7 mg of methyl sulphonamide are added and allowed to react for 15 minutes. A solution of 150 mg of the compound of the preceding step 1E) dissolved in 5 ml of anhydrous DMF is added. The mixture is allowed to return to RT and then the mixture is left for 3 hours at 60° C. The DMF is evaporated under vacuum, the residue is redissolved in CH₂Cl₂, washed with H₂O, dried over MgSO₄ and evaporated. 93 mg of the desired compound are obtained after chromatography (cyclohexane/EtOAc).

LCMS: MH+ (—OMe)=485.0, tr=1.96.

1G) 5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-2-(3-methanesulphonylaminopropyl)-1H-pyrrole-3-carboxylic acid

3.43 g of the product obtained in step 1F) are dissolved in 200 ml of methanol. 20 ml of water are added and the mixture is kept stirred for 17 hours at 65° C. The methanol is partially evaporated, and then the mixture is diluted with CH₂Cl₂ and acidified with concentrated HCl to pH=1 while cooling. The organic phase is dried over MgSO₄, filtered and evaporated, and 3.24 g (97%) of a white solid are obtained.

LCMS: MH+ (—OMe)=485.1, tr=1.74.

Preparation 2 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid 2A) Methyl ester of 4-benzyloxy-3-oxobutyric acid

13.28 g of NaH are introduced into 200 ml of dry THF. The mixture is cooled to about 0° C. and then 25 g of methyl ester of 4-chloro-3-oxobutyric acid are added dropwise. 17 ml of benzyl alcohol are then added dropwise. The solution takes on a red colour. The mixture is kept stirred at RT for 17 hours and the reaction mixture is poured into 120 ml of 2N HCl. The mixture is extracted with ether. The organic phase is dried over MgSO₄ and evaporated. After chromatography (eluent: cyclohexane/EtOAc), 23.5 g of product are obtained.

2B) Methyl ester of 4-benzyloxy-2-[2-(2,4-dichlorophenyl)-2-oxoethyl]-3-oxobutyric acid

4.13 g of NaH are introduced into 500 ml of dry THF, cooled to 0° C. 23 g of the compound obtained in step 2A) are added dropwise. The mixture is kept stirred for 30 minutes, and then 27.7 g of 2,4-dichlorophenacyl bromide are added dropwise. The mixture is allowed to react for 3 hours at 0° C., and then the temperature is raised to RT for 17 hours. 150 ml of 2N HCl are added, after cooling, followed by extraction with ether, washing with H₂O, drying and evaporation. 26 g of product are obtained whose analysis by LCMS confirms the structure.

2C) Methyl ester of 2-benzyloxymethyl-1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-1H-pyrrole-3-carboxylic acid

To a round-bottomed flask are added 3.8 g obtained in step 2B), 15 ml of CH₂Cl₂ and 4 g of Montmorillonite K10. The mixture is kept stirred under nitrogen for 72 hours. The mixture is filtered, rinsed with CH₂Cl₂, washed with dilute HCl, dried and the organic phase is evaporated. After chromatography, 3 g of the desired pyrrole are obtained.

2D) Methyl ester of 1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid

8 g of the product of step 2C) in 150 ml of CH₂Cl₂ are dissolved in a round-bottomed flask. The mixture is cooled to 0° C. and 13 g of BCl₃-dimethyl sulphide complex dissolved beforehand in 50 ml of CH₂Cl₂ are added dropwise. After reacting for 1 hour, the mixture is neutralized with solid NaHCO₃ until the gaseous release ceases. The organic phase is dried, and 4.5 g of oil are obtained after chromatography whose NMR spectrum confirms the structure.

2E) 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carboxylic acid

2.7 g of the compound of step 2D) are reacted with 1 g of LiOH in a mixture of dioxane and H₂O 90/10 for 17 hours at 60° C. After evaporation, the mixture is redissolved in CH₂Cl₂, washed with a solution pH=2, and purified by chromatography. 350 mg of the desired product are obtained whose structure is confirmed by LCMS and NMR.

EXAMPLES Example 1 1-{[1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-{3-[(methylsulphonyl)amino]propyl}-1H-pyrrol-3-yl]carbonyl}-4-phenyl-4-piperidinecarboxamide

0.5 g of the compound obtained in step 1G) of Preparation 1, 0.7 ml of DIPEA and 350 mg of 4-phenylpiperidine-4-carboxamide acid in 10 ml of CH₂Cl₂ are introduced into a round-bottomed flask under nitrogen. The mixture is cooled to 0° C. 3.25 g of TBTU are added and the mixture is kept stirred for 30 minutes. The mixture is washed with saturated NaHCO₃, buffer 2, and then with a saturated NaCl solution. The mixture is dried over MgSO₄, filtered and evaporated.

The crude product is chromatographed on silica (eluent CH₂Cl₂/MeOH) to give 0.48 g of the desired compound whose structure is confirmed by LCMS and NMR.

LC/MS (B): MH⁺=687, tr=10. 16.

Example 2 1′-[1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-hydroxymethyl-1H-pyrrole-3-carbonyl]-[1,4′]bipiperidinyl-4′-carboxamide

There is dissolved 0.3 g of the product obtained in step 2E) of Preparation 2 in 20 ml of CH₂Cl₂, with 27 ml of DIPEA. 0.16 g of [1,4]bipiperidinyl-4′-carboxamide and 0.22 g of TBTU are then added. The mixture is kept stirred for 1 hour and then diluted with 50 ml of CH₂Cl₂, washed with a buffer solution pH=2, a saturated NaHCO₃ solution, the organic phase is dried and evaporated. 350 mg of the solid compound are obtained after chromatography whose structure is confirmed by LCMS and NMR.

Example 3 4-(4-Chlorophenyl)-1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxypropyl)-1H-pyrrol-3-yl]carbonyl}piperidine-4-carboxamide 3a) 1-(4-Chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxypropyl)-1H-pyrrole-3-carboxylic acid

In a round-bottomed flask under nitrogen, 5 g of the compound obtained in step 1D) of Preparation 1 are dissolved in 180 ml of water and 20 ml of methanol. 5 g of LiOH are added and the mixture is heated at 60° C. for 17 hours. The solvent is evaporated under vacuum and the residue obtained is redissolved in 100 ml of CH₂Cl₂ and 50 ml of water. After acidification with HCl to pH=1, drying of the organic phase with MgSO₄, filtration and then evaporation, 4.67 g of an acid compound are obtained.

3b) 4-(4-Chlorophenyl)-1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxypropyl)-1H-pyrrol-3-yl]carbonyl}piperidine-4-carboxamide

Into a round-bottomed flask under nitrogen are introduced 300 mg of the acid obtained in step 3a) in 30 ml of DMF, 246 mg of 4-(4-chlorophenyl)piperidine-4-carboxamide (prepared according to the procedure described in patent application US 2005/0070549, in particular in Example 460, paragraphs 1394 to 1397), 0.62 ml of DIPEA and 250 mg of TBTU.

The mixture is kept stirred for 17 hours at RT. The mixture is evaporated, taken up in CH₂Cl₂, washed with N HCl, dried over MgSO₄, filtered and evaporated. The crude product is chromatographed on silica (eluent CH₂Cl₂/MeOH) to give 0.32 g of the desired compound whose structure is confirmed by LCMS and NMR.

Table 1 shows the chemical structures of some compounds according to the invention and their physical properties (analysis by LC/UV/MS coupling: liquid chromatography/UV detection/mass spectrometry). In this table, Me means methyl. The compounds listed are prepared according to the methods of preparation described above and in particular by following procedures similar to those described in Examples 1 to 3.

TABLE 1

LC/MS characterization MH+; tr; Compound A-R₉ NR₁R₂ (condition) 1 —(CH₂)₃—OH

MH+ = 617 tr = 7.34 (A) 2 —(CH₂)₃—NHSO₂CF₃

MH+ = 694 tr = 1.42 (C) 3 —(CH₂)₃—NHSO₂CF₃

NH+ = 748 tr = 8.46 (A) 4 —(CH₂)₃—OH

MH+ = 610 tr = 7.5 (D) 5

MH+ = 663 tr = 9.5 (B) 6 —(CH₂)₃—NHSO₂Me

MH+ = 687 tr = 10.16 (A) 7 —(CH₂)₃—O—(CH₂)₂—OH

MH+ = 661 tr = 7.36 (A) 8 —CH₂—OH

MH+ = 589 tr = 1.36 (C) 9 —(CH₂)₄—OH

MH+ = 631 tr = 1.41 (E) 10 —(CH₂)₄—OH

MH+ = 658 tr = 1.88 (E) 11 —(CH₂)₂—OH

MH+ = 630 tr = 1.87 (E) 12 —(CH₂)₂—OH

MH+ = 603 tr = 1.36 (E) 13 —(CH₂)₄—OH

MH+ = 624 tr = 1.77 (E) 14 —(CH₂)₂—OH

MH+ = 596 tr = 1.76 (E) 15 —(CH₂)₄—OH

MH+ = 659 tr = 1.49 (E) 16 —(CH₂)₂—OH

MH+ = 631 tr = 1.44 (E) 17 —(CH₂)₄—OH

MH+ = 667 tr = 1.61 (E) 18 —(CH₂)₂—OH

MH+ = 639 tr = 1.58 (E) 19 —(CH₂)₄—OH

MH+ = 653 tr = 1.73 (E) 20 —(CH₂)₂—OH

MH+ = 625 tr = 1.71 (E) 21 —(CH₂)₄—OH

MH+ = 659 tr = 1.48 (E) 22 —(CH₂)₂—OH

MH+ = 643 tr = 1.44 (E) 23 —(CH₂)₄—OH

MH+ = 671 tr = 1.49 (E) 24 —(CH₂)₂—OH

MH+ = 631 tr = 1.43 (E) 25 —(CH₂)₄—OH

MH+ = 671 tr = 1.51 (E) 26 —(CH₂)₂—OH

MH+ = 643 tr = 1.46 (E) 27 —(CH₂)₃—NHSO₂CH₃

28 —(CH₂)₃—OH

29 —(CH₂)₃—NHSO₂CH₃

MH+ = 721 tr = 1.94 (E) 30 —(CH₂)₃—OH

MH+ = 644 tr = 1.94 (E) 31 —(CH₂)₃—OH

MH+ = 653 tr = 1.66 (E) 32 —(CH₂)₃—NHSO₂CH₃

MH+ = 716 tr = 1.75 (E) 33 —(CH₂)₃—NHSO₂CH₃

MH+ = 730 tr = 1.64 (E) 34 —(CH₂)₃—OH

MH+ = 594 tr = 1.66 (E) 35 —(CH₂)₃—OH

MH+ = 587 tr = 1.29 (E) 36 —(CH₂)₃—OH

MH+ = 562 tr = 1.37 (E) 37 —(CH₂)₄—CONH₂

MH+ = 680 tr = 1.65 (E) 38 —(CH₂)₂—CONH₂

MH+ = 652 tr = 1.59 (E) 39 —(CH₂)₂—CONH₂

MH+ = 623 tr = 1.64 (E) 40 —(CH₂)₄—CONH₂

NH+ = ? tr = ? (E) 41 —(CH₂)₃—OH

MH+ = 624 tr = 1.64 (E) 42 —(CH₂)₃—CONH₂

MH+ = 621 tr = 1.55 (E) 43 —(CH₂)₃—NHSO₂Me

MH+ = 680 tr = 1.4 (E) 44 —(CH₂)₃—OH

MH+ = 603 tr = 1.39 (E) 45 —(CH₂)₃—NHSO₂Me

MH+ = 626 tr = 1.81 (E) 46 —(CH₂)₃—OH

MH+ = 549 tr = 1.8 (E) 47 —(CH₂)₃—NHSO₂Me

MH+ = 705 tr = 1.83 (E) 48 —(CH₂)₃—OH

MH+ = 628 tr = 1.81 (E) 49 —(CH₂)₄—CONH₂

MH+ = 669 tr = 1.72 (E) 50 —(CH₂)₃—OH

MH+ = 612 tr = 1.69 (E)

The analyses carried out by NMR for some compounds are given below:

Compound 1

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.20-1.99: u.c.: 10H, 2.52-3.02: u.c.: 8H, 3.17: t: 2H, 3.55: bd: 2H, 4.41: bd: 2H, 6.38: s: 1H, 7.22: d: 2H, 7.27-7.31: u.c.: 2H, 7.43: d: 2H, 7.53: d: 1H, 8.18: bs: 2H, 10.23: t: 1H.

Compound 2

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 1.30-1.58: u.c.: 8H, 1.73: mt: 2H, 1.88: bd: 2H, 2.45: bt: 4H, 2.62: t: 2H, 2.73: q: 2H, 2.78: s: 3H, 3.35: bs: 2H; 3.86: bm: 2H, 6.37: s: 1H, 6.93: d: 1H, 6.98-7.11: 2s: 2H, 7.20-7.37: u.c.: 4H, 7.45: d: 2H, 7.58: d: 1H.

Compound 3

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.27-1.97: u.c.: 12H, 2.45: bs: 4H, 2.65: t: 2H, 2.92: t: 2H, 3.38: mt: 2H, 3.85: bd: 2H, 6.38: s: 1H, 6.96-7.13: 2s: 2H, 7.17-7.39: u.c.: 4H, 7.46: d: 2H, 7.58: d: 1H, 8.18: bs: 2H, 10.23: t: 1H.

Compound 4

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.31: quin: 2H, 1.79: mt: 2H, 2.52: mt: 2H, 2.62: t: 2H, 3.15: q: 2H, 3.23: bs: 2H, 4.10: bd: 2H, 4.44: t: 1H, 6.38: s: 1H, 7.07: s: 1H, 7.17-7.52: u.c.: 12H, 7.58: d: 1H.

Compound 5

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 1.63: quin: 2H, 1.74-2.06: u.c.: 6H, 2.53: mt: 2H, 2.70: t: 2H, 2.90: bs: 6H, 3.38: bt: 2H, 4.05: dt: 2H, 6.41: s: 1H, 6.85: bs: 2H, 7.18-7.58: u.c.: 12H.

Compound 6

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 1.41: quin: 2H, 1.81: mt: 2H, 2.53: u.c.: 2H, 2.62: t: 2H, 2.72: q: 2H, 2.74: s: 3H, 3.24: bs: 2H, 4.10: bs: 2H, 6.40: s: 1H, 6.91: t: 1H, 7.07: s: 1H, 7.18-7.60: u.c.: 13H.

Compound 7

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 1.30-1.99: u.c.: 10H, 2.53-2.71: u.c.: 4H, 2.74-3.01: mt: 4H, 3.10-3.26: mt: 4H, 3.38: t: 2H, 3.57: bd: 2H, 4.38: bd: 2H, 6.39: s: 1H, 7.05: bs: 2H, 7.17-7.38: mt: 4H, 7.45: d: 2H, 7.56: s: 1H.

Compound 8

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.60: mt: 6H, 1.64-1.97: u.c.: 4H, 2.46: bs: 4H, 3.35: t: 2H, 3.85: d: 2H, 4.31: d: 2H, 4.92: t: 1H, 6.42: s: 1H, 7.08: d: 2H, 7.21-7.51: mt: 6H, 7.60: d: 1H.

Compound 10

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.05-1.30: u.c.: 4H, 1.77: t: 2H, 2.37-2.54: u.c.: 2H, 2.54-2.67: u.c.: 2H, 3.06-3.32: u.c.: 4H, 3.90-4.18: u.c.: 2H, 4.22: t: 1H, 6.38: s: 1H, 7.12: s: 1H, 7.19-7.34: u.c.: 5H, 7.37-7.51: u.c.: 6H, 7.58: d: 1H.

Compound 13

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.02-1.28: u.c.: 4H, 1.78: t: 2H, 2.41-2.55: u.c.: 2H, 2.61: t: 2H, 3.14: q: 2H, 3.17-3.33: u.c.: 2H, 4.01-4.16: u.c.: 2H, 4.21: t: 1H, 6.38: s: 1H, 7.08: s: 1H, 7.16-7.54: u.c.: 12H, 7.58: d: 1H.

Compound 16

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.60: d: 2H, 1.82: t: 2H, 2.27-2.48: u.c.: 3H, 2.52-2.66: u.c.: 2H, 2.74: t: 2H, 3.20-3.33: u.c.: 2H, 3.34-3.56: u.c.: 2H, 3.76-3.95: u.c.: 2H, 4.76: t: 1H, 6.35: s: 1H, 7.11: s: 1H, 7.19-7.37: u.c.: 5H, 7.40-7.53: u.c.: 2H, 7.58: d: 1H.

Compound 18:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.66-2.06: u.c.: 8H, 2.54-2.67: u.c.: 4H, 2.75: t: 2H, 3.21-3.35: u.c.: 2H, 3.37-3.50: u.c.: 2H, 3.73-3.95: u.c.: 2H, 4.76: t: 1H, 6.38: s: 1H, 7.16: s: 2H, 7.22-7.39: u.c.: 4H, 7.47: d: 2H, 7.58: d: 1H.

Compound 20:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.66-1.82: u.c.: 2H, 1.84-1.99: u.c.: 2H, 2.13-2.31: u.c.: 2H, 2.74: t: 2H, 2.85: t: 2H, 3.08: t: 2H, 3.24-3.34: u.c.: 2H, 3.47-3.61: u.c.: 2H, 3.61-3.72: u.c.: 2H, 4.75: t: 1H, 6.38: s: 1H, 7.21: s: 1H, 7.26: dd: 4H, 7.33: dd: 1H, 7.46: d: 2H, 7.58: d: 1H.

Compound 24:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.20-1.38: u.c.: 4H, 1.63-1.98: u.c.: 4H, 2.37-2.48: u.c.: 4H, 2.73: t: 2H, 3.20-3.33: u.c.: 2H, 3.32-3.51: u.c.: 2H, 3.73-3.93: u.c.: 2H, 4.76: t: 1H, 6.38: s: 1H, 7.07: d: 2H, 7.21-7.37: u.c.: 4H, 7.47: d: 2H, 7.58: d: 1H.

Compound 27:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 0.85: s: 6H, 1.25-1.34: u.c.: 4H, 1.35-1.50: u.c.: 2H, 1.62-2.04: u.c.: 4H, 2.36-2.48: u.c.: 4H, 2.56-2.67: u.c.: 2H, 2.68-2.78: u.c.: 2H, 2.77: s: 3H, 3.31-3.50: u.c.: 2H, 3.72-3.95: u.c.: 2H, 6.38: s: 1H, 6.94: t: 1H, 7.02-7.15: u.c.: 2H, 7.25: d: 2H, 7.29-7.34: u.c.: 2H, 7.46: d: 2H, 7.58: d: 1H.

Compound 28:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 0.85: s: 6H, 1.18-1.52: u.c.: 6H, 1.65-2.09: u.c.: 4H, 2.37-2.47: u.c.: 4H, 2.56-2.67: u.c.: 2H, 3.15: q: 2H, 3.33-3.46: u.c.: 2H, 3.77-3.93: u.c.: 2H, 4.48: t: 1H, 6.36: s: 1H, 7.02-7.16: u.c.: 2H, 7.19-7.34: u.c.: 4H, 7.46: d: 2H, 7.58: d: 1H.

Compound 29:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.29-1.50: u.c.: 2H, 1.65-1.90: u.c.: 2H, 2.37-2.51: u.c.: 2H, 2.66-2.81: u.c.: 5H, 3.05-3.28: u.c.: 2H, 3.86-4.30: u.c.: 2H, 6.40: s: 1H, 6.92: t: 1H, 7.10-7.20: u.c.: 1H, 7.21-7.37: u.c.: 6H, 7.37-7.55: u.c.: 7H, 7.59: d: 1H.

Compound 30:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.23-1.40: u.c.: 2H, 1.68-1.87: u.c.: 2H, 2.37-2.50: u.c.: 2H, 2.55-2.68: u.c.: 2H, 3.14: q: 2H, 3.17-3.31: u.c.: 2H, 3.93-4.25: u.c.: 2H, 4.46: t: 1H, 6.39: s: 1H, 7.16: s: 1H, 7.20-7.34: u.c.: 5H, 7.42: s, 6H, 7.59: d: 1H.

Compound 31:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.25-1.43: u.c.: 2H, 1.65-2.08: u.c.: 8H, 2.53-2.72: u.c.: 6H, 3.15: q: 2H, 3.36-3.57: u.c.: 2H, 3.70-3.91: u.c.: 2H, 4.49: t: 1H, 6.37: s: 1H, 7.17: s: 2H, 7.24: d: 2H, 7.30: s: 1H, 7.32: d: 1H, 7.46: d: 2H, 7.58: d: 1H.

Compound 32:

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 1.33-1.49: u.c.: 2H, 1.69-1.84: u.c.: 2H, 1.86-2.00: u.c.: 2H, 2.14-2.31: u.c.: 2H, 2.58-2.66: u.c.: 2H, 2.73: q: 2H, 2.78: s: 3H, 2.85: t: 2H, 3.08: t: 2H, 3.48-3.60: u.c.: 2H, 3.61-3.76: u.c.: 2H, 6.39: s: 1H, 6.93: t: 1H, 7.20: s: 1H, 7.22-7.36: u.c.: 5H, 7.46: d: 2H, 7.58: d: 1H.

Compound 33:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.31-1.55: u.c.: 2H, 1.66-2.09: u.c.: 8H, 2.53-2.67: u.c.: 6H, 2.73: q: 2H, 2.77: s: 3H, 3.38-3.63: u.c.: 2H; 3.72-3.94: u.c.: 2H, 6.38: s: 1H, 6.94: t: 1H, 7.17: s: 2H, 7.25: d: 2H, 7.29-7.35: u.c.: 2H, 7.47: d: 2H, 7.59: d: 1H.

Compound 34:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm): 1.22-1.40: u.c.: 2H, 1.66-1.91: u.c.: 2H, 2.42-2.56: u.c.: 2H, 2.56-2.68: u.c.: 2H, 3.14: q: 2H, 3.11-3.32: u.c.: 2H, 3.96-4.25: u.c.: 2H, 4.48: t: 1H, 6.35: s: 1H, 7.05-7.20: u.c.: 2H, 7.20-7.30: u.c.: 4H, 7.30-7.57: u.c.: 8H.

Compound 35:

¹H NMR: DMSO-d6 (400 MHz): δ (ppm): 0.00-0.16: u.c.: 2H, 0.35-0.50: u.c.: 2H, 0.80-0.96: u.c.: 1H, 1.27-1.40: u.c.: 2H, 1.52-1.65: u.c.: 2H; 1.73-1.86: u.c.: 2H, 2.09: br. s.: 1H, 2.20: d: 2H, 2.63: t: 2H, 3.17: q: 2H, 3.39-3.64: u.c.: 2H, 3.70-3.93: u.c.: 2H, 4.49: t: 1H, 6.29: s: 1H, 6.99: s: 1 H, 7.08-7.17: u.c.: 1H, 7.23: d; 2H, 7.27-7.37: u.c.: 2H, 7.39: dd: 1H, 7.44: d 2H.

Compound 36:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.24-1.40: u.c.: 2H, 1.40-1.62: u.c.: 2H, 1.64-1.84: u.c.: 2H, 2.31-2.46: u.c.: 1H, 2.61: t: 2H, 2.80-3.04: u.c.: 2 H, 3.04-3.24: u.c.: 4H, 3.37: q: 2H, 4.15-4.39: u.c.: 2H, 4.47: t: 1H, 4.63: t: 1H, 6.29: s: 1H, 7.06-7.19: u.c.: 1H, 7.24: d: 2H, 7.29-7.50: u.c.: 4H, 7.81: s: 1H

Compound 37:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.06-1.40: u.c.: 4H, 1.59-2.05: u.c.: 6H, 2.06-2.36: u.c.: 2H, 2.53-2.67: u.c.: 2H, 2.74-2.95: u.c.: 2H, 3.01-3.20: u.c.: 2H, 3.46-3.77: u.c.: 4H, 6.37: s: 1H, 6.58: s: 1H, 7.12: s: 1H, 7.18-7.40: u.c.: 6H, 7.46: d: 2H, 7.57: d: 1H.

Compound 38:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.63-2.00: u.c.: 4H, 2.02-2.39: u.c.: 4H, 2.66-2.80: u.c.: 2H, 2.80-2.94: u.c.: 2H, 3.10: t, 2H, 3.46-3.78: u.c.: 4 H, 6.38: s: 1H, 6.65: s: 1H, 7.14: s: 1H, 7.18-7.38: u.c.: 7H, 7.46: d: 2H, 7.58: d: 1H.

Compound 39:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.70-1.90: u.c.: 2H, 2.01-2.16: u.c.: 2H, 2.45-2.58: u.c.: 2H, 2.67-2.81: u.c.: 2H, 3.34: s: 2H, 3.90-4.21: u.c.: 2H, 6.37: s: 1H, 6.63: s: 1H, 7.03-7.17: u.c.: 2H, 7.18-7.52: u.c.: 12H, 7.57: d: 1H.

Compound 40:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.02-1.42: u.c.: 4H, 1.65-1.96: u.c.: 4H, 2.38-2.64: u.c.: 4H, 3.08-3.38: u.c.: 2H, 3.95-4.20: u.c.: 2H, 6.38: s: 1H, 6.56: s: 1H, 7.02-7.16: u.c.: 2H, 7.17-7.52: u.c.: 12H, 7.58: d: 1H.

Compound 41:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.24-1.40: u.c.: 2H, 1.63-1.82: u.c.: 2H, 1.82-1.96: u.c.: 2H, 2.09-2.33: u.c.: 2H, 2.55-2.68: u.c.: 2H, 2.79-2.90: u.c.: 2H, 3.05: d: 1H, 3.11-3.23: u.c.: 3H, 3.45-3.75: u.c.: 4H, 4.47: t: 1H, 6.33: s: 1H, 7.08-7.29: u.c.: 5H, 7.30-7.50: u.c.: 4H.

Compound 42:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.31-1.54: u.c.: 2H, 1.69-1.93: u.c.: 4H, 2.42-2.69: u.c.: 4H, 3.07-3.28: u.c.: 2H, 4.01-4.32: u.c.: 2H, 6.35: s: 1H, 6.60: s: 1H, 7.04-7.33: u.c.: 10H, 7.35-7.54: u.c.: 5H.

Compound 43:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm)-0.01-0.12: u.c.: 2H, 0.34-0.46: u.c.: 2H, 0.75-0.96: u.c.: 1H, 1.30-1.49: u.c.: 2H, 1.49-1.67: u.c.: 2H, 1.69-1.88: u.c.: 2H, 2.07: br. s.: 1H, 2.13-2.29: u.c.: 2H, 2.56-2.67: u.c.: 2 H, 2.72: q: 2H, 2.78: s: 3H, 3.40-3.64: u.c.: 2H, 3.66-3.91: u.c.: 2H, 6.36: s: 1H; 6.94: t: 1H, 6.99-7.05: u.c.: 1H, 7.18-7.34: u.c.: 5H, 7.45: s: 2H, 7.58: d: 1H.

Compound 44:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 0.02-0.14: u.c.: 2H, 0.33-0.45: u.c.: 2H, 0.74-0.94: u.c.: 1H, 1.22-1.38: u.c.: 2H, 1.50-1.66: u.c.: 2H, 1.69-1.86: u.c.: 2H, 2.19: d: 2H, 2.62: t: 2H, 3.16: q: 2H, 3.41-3.66: u.c.: 2H, 3.68-3.92: u.c.: 2H, 4.45: t: 1H, 6.34: s: 1H, 7.02: s: 1H, 7.17-7.36: u.c.: 5H, 7.46: d: 2H, 7.58: d: 1H.

Compound 45:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 0.94-1.15: u.c.: 2H, 1.17-1.32: u.c.: 2H, 1.31-1.62: u.c.: 5H, 1.61-1.81: u.c.: 2H, 2.62: t: 2H, 2.73: q: 2H, 2.78: s: 3H, 2.80-3.03: u.c.: 2H, 3.38: q: 2H, 4.11-4.35: u.c.: 2H, 4.35: t: 1H, 6.33: s: 1H, 6.94: t: 1H, 7.19-7.34: u.c.: 4H, 7.46: d: 2H, 7.58: d: 1H.

Compound 46:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 0.92-1.15: u.c.: 2H, 1.15-1.60: u.c.: 7H, 1.70: d: 2H, 2.62: t: 2H, 2.66-3.06: u.c.: 2H, 3.17: q: 2H, 3.38: q: 2H, 4.16-4.33: u.c.: 2H, 4.35: t: 1H, 4.48: t: 1H, 6.31: s: 1H, 7.24: d: 2H, 7.28-7.37: u.c.: 2H, 7.46: d: 2H, 7.58: d: 1H.

Compound 47:

¹H NMR: DMSO-d6 (400 MHz): δ (ppm) 1.33-1.49: u.c.: 2H, 1.73-1.89: u.c.: 2H, 2.46-2.54: u.c.: 2H, 2.62: t: 2H, 2.72: q: 2H, 2.75: s: 3H, 3.02-3.27: u.c.: 2H, 3.92-4.31: u.c.: 2H, 6.40: s: 1H, 6.90: t: 1H, 7.10: s: 1H, 7.17: t: 2 H, 7.21-7.38: u.c.: 5H, 7.39-7.50: u.c.: 4H, 7.58: s: 1H.

Compound 48:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.24-1.42: u.c.: 2H, 1.66-1.86: u.c.: 2H, 2.43-2.56: u.c.: 2H, 2.62: t: 2H, 3.15: q: 2H, 3.14-3.26: u.c.: 2H, 3.99-4.21: u.c.: 2H, 4.43: t: 1H, 6.38: s: 1H, 7.10: s: 1H, 7.13-7.37: u.c.: 7H, 7.38-7.52: u.c.: 4H, 7.58: d: 1H.

Compound 49:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.05-1.36: u.c.: 4H, 1.66-1.90: u.c.: 4H, 2.42-2.51: u.c.: 2H, 2.54-2.69: u.c.: 2H, 3.04-3.28: u.c.: 2H, 3.93-4.23: u.c.: 2H, 6.38: s: 1H, 6.57: s: 1H, 7.03-7.36: u.c.: 9H, 7.40-7.54: u.c.: 4H, 7.57: d: 1H.

Compound 50:

¹H NMR: DMSO-d6 (250 MHz): δ (ppm) 1.21-1.44: u.c.: 2H, 1.66-1.88: u.c.: 2H, 2.44-2.54: u.c.: 2H, 2.62: t: 2H, 3.15: q: 2H, 3.15-3.28: u.c.: 2H, 3.97-4.19: u.c.: 2H, 4.44: t: 1H, 6.34: s: 1H, 7.03-7.28: u.c.: 7H, 7.30-7.51: u.c.: 6H.

The compounds of formula (I) possess a very good affinity in vitro (IC₅₀≦5.10⁻⁷M) for the CB₁ cannabinoid receptors under the experimental conditions described by M. Rinaldi-Carmona et al. (FEBS Letters, 1994, 350, 240-244).

The antagonist nature of the compounds of formula (I) was demonstrated in vitro by the results obtained in the adenylate cyclase inhibition models as described in M. Bouaboula et al., J. Biol. Chem., 1995, 270, 13973-13980, M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 1996, 278, 871-878 and M. Bouaboula et al., J. Biol. Chem., 1997, 272, 22330-22339.

The weak penetration of the compounds of formula (I) at the level of the blood-brain barrier (BBB) was evaluated in vivo by:

-   -   Measurement (1): the quantification of the compounds of         formula (I) (unchanged) in samples of mouse brain after         intravenous or oral administration, with the aid of an         analytical technique (LC-MS/MS).

${The}\mspace{14mu} {ratio}\mspace{14mu} \frac{{quantity}\mspace{14mu} {present}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {brain}}{{quantity}\mspace{14mu} {present}\mspace{14mu} {in}\mspace{14mu} {the}\mspace{14mu} {plasma}}\mspace{14mu} {less}\mspace{14mu} {than}\mspace{14mu} 0.2\mspace{14mu} {indicates}\mspace{14mu} a\mspace{14mu} {weak}\mspace{14mu} {penetration}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {compound}\mspace{14mu} {at}\mspace{14mu} {the}\mspace{14mu} {level}\mspace{14mu} {of}\mspace{14mu} {the}\mspace{14mu} {{brain}.}$

-   -   Measurement (2): the measurement of the interaction of the         compounds of formula (I) with the CB₁ receptors present in the         brain in mice with the aid of an ex vivo test of binding of         [3H]-CP55940 (CB₁ agonist) after administration by the         intravenous route (10 mg/kg) as described in M. Rinaldi-Carmona         et al., FEBS Letters, 1994, 350, 240-244 and M. Rinaldi-Carmona         et al., Life Sciences, 1995, 56, 1941-1947, M. Rinaldi-Carmona         et al., J. Pharmacol. Exp. Ther., 2004, 310, 905-914.     -   A percentage inhibition of the binding of [3H]-CP55940 at the         level of the brain of less than 50% at 10 mg/kg indicates a weak         penetration at the level of the brain. Preferably, this         percentage is less than 40% and more preferably less than 30%.     -   Measurement (3): the measurement of the blocking, by the         compounds of formula (I), of the hypothermic effect induced by         an agonist of the CB₁ receptors (CP55940), after administration         by the intravenous route, as described in Rinaldi-Carmona M. et         al., JPET 2004, 310, 905-914.     -   A percentage reversion of the effect of CP55940 of less than or         equal to 60% at 10 mg/kg indicates a weak penetration at the         level of the brain. Preferably, this percentage is less than 40%         and more preferably less than 30%.

The interaction of the compounds of formula (I) according to the invention with the CB₁ receptors present at the periphery was demonstrated in mice by measuring the blocking of the inhibitory effect induced by an agonist of the CB₁ receptors (CP55940) on the gastrointestinal transit, after oral administration, as described in M. Rinaldi-Carmona et al., J. Pharmacol. Exp. Ther., 2004, 310, 905-914. A percentage reversion of the effect of CP55940 greater than 50% at 10 mg/kg indicates a significant antagonist power at the level of the CB₁ receptors present at the periphery. Preferably, the percentage reversion is between 70% and 100%.

By way of examples, the following measurements were performed for compound Nos. 13, 14, 17 and 30 of Table 1.

% inhibition of % reversion the binding of of the effect Ratio: [3H]-CP55940 of CP55940 Quantity present in the brain, by % reversion of the on the GIT in the brain the iv route at hypothermic effect by the po Quantity present 10 mg/kg of CP55940, by route at in the plasma [CB₁ receptors the iv route at 10 mg/kg [iv route at present in the 10 mg/kg [CB₁ 3 mg/kg, brain according [CB₁ receptors receptors according to to present in the present at measurement measurement brain, according to the (1)] (2)]. measurement (3)]. periphery]. Control: 1.8 100% 100% [effective dose 50 100% rimonabant (ED₅₀) = 0.3 mg/kg] Compound 5% 58% 100% No. 13 Compound 27% 60% 85% No. 14 Compound 23% 60% 97% No. 17 Compound 0.06 21% 32% 74% No. 30

The compounds of formula (I) are compatible with their use as a medicament.

Thus, according to another of its aspects, the subject of the invention is medicaments for human or veterinary medicine which comprise a compound of formula (I), or an addition salt thereof with a pharmaceutically acceptable acid.

Thus, the compounds according to the invention may be used in humans or in animals (in particular in mammals including, without limitation, dogs, cats, horses, bovines, sheep) in the treatment or prevention of diseases involving the CB₁ cannabinoid receptors.

For example and without limitation, the compounds of formula (I) are useful as psychotropic medicaments, in particular for the treatment of psychiatric disorders including anxiety, depression, mood disorders, insomnia, delirium disorders, obsessive disorders, psychoses in general, schizophrenia, attention deficit hyperactivity disorders (ADHD) in hyperkinetic children and for the treatment of disorders linked to the use of psychotropic substances, in particular in the case of substance abuse and/or of dependence on a substance, including alcohol dependence and nicotine dependence.

The compounds of formula (I) according to the invention may be used as medicaments for the treatment of migraine, stress, diseases of psychosomatic origin, panic attacks, epilepsy, motion disorders, in particular dyskinesia or Parkinson's disease, tremors and dystonia.

The compounds of formula (I) according to the invention may also be used as medicaments in the treatment of memory disorders, cognitive disorders, in particular in the treatment of senile dementia, Alzheimer's disease, and in the treatment of attention or vigilance disorders.

Furthermore, the compounds of formula (I) may be useful as neuroprotectants, in the treatment of ischaemia, cranial traumas and the treatment of acute or chronic neurodegenerative diseases: including chorea, Huntington's chorea, Tourrette's syndrome.

The compounds of formula (I) according to the invention may be used as medicaments in the treatment of pain: neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin, pain induced by an anticancer treatment.

The compounds of formula (I) according to the invention may be used as medicaments in human or veterinary medicine in the prevention and treatment of appetite disorders, craving disorders (for sugars, carbohydrates, drugs, alcohol or any appetizing substance) and/or alimentary canal disorders, in particular for the treatment of obesity or bulimia and for the treatment of type II diabetes or non-insulin-dependent diabetes and for the treatment of dyslipidemia, and of metabolic syndrome. Thus, the compounds of formula (I) according to the invention are useful in the treatment of obesity and of the risks associated with obesity, in particular the cardiovascular risks.

Furthermore, the compounds of formula (I) according to the invention may be used as medicaments in the treatment and prevention of gastrointestinal disorders, diarrhoeal disorders, ulcers, emesis, bladder and urinary disorders, liver diseases of alcohol or non-alcohol origin such as chronic cirrhosis, fibrosis, hepatic steatosis, steatohepatitis; and disorders of endocrine origin, cardiovascular disorders, hypotension, atherosclerosis, haemorrhagic shock, septic shock, asthma, chronic bronchitis, chronic obstructive pulmonary disease, Raynaud's syndrome, glaucoma, fertility disorders, premature labour, abortion, inflammatory phenomena, immune system diseases, in particular autoimmune and neuroinflammatory diseases such as rheumatoid arthritis, reactive arthritis, diseases causing demyelinization, multiple sclerosis, infectious and viral diseases such as encephalitis, stroke and as medicaments for anticancer chemotherapy, for the treatment of Guillain-Barré syndrome and for the treatment of bone diseases and of osteoporosis. Furthermore, the compounds of formula (I) according to the invention may be used for their protective effects against drug-induced cardiotoxicity.

According to the present invention, the compounds of formula (I) are most particularly useful for the preparation of medicaments useful for the prevention and treatment of psychiatric disorders, in particular schizophrenia, attention and vigilance disorders, attention deficit and hyperactivity disorders (ADHD) in hyperkinetic children; for the prevention and treatment of memory deficiencies and cognitive disorders; dependence and withdrawal from a substance, in particular alcohol dependence, nicotine dependence, withdrawal from alcohol and smoking cessation; acute or chronic neurodegenerative diseases.

More particularly, the compounds of formula (I) according to the present invention are useful in the preparation of medicaments useful in the treatment and prevention of appetite disorders, craving disorders, metabolism disorders, obesity, type II diabetes, metabolic syndrome, dyslipidemia, gastrointestinal disorders, inflammatory phenomena, diseases of the immune system, psychotic disorders, alcohol dependence, nicotine dependence.

According to one of its aspects, the present invention relates to the use of a compound of formula (I) and of its pharmaceutically acceptable salts for the treatment of disorders and diseases indicated above.

According to another of its aspects, the present invention relates to pharmaceutical compositions comprising, as active ingredient, a compound according to the invention. These pharmaceutical compositions contain an effective dose of at least one compound according to the invention, or a pharmaceutically acceptable salt of the said compound, and at least one pharmaceutically acceptable excipient.

The said excipients are chosen according to the pharmaceutical dosage form and the mode of administration desired, from the customary excipients which are known to persons skilled in the art.

Pharmaceutical compositions according to the present invention may contain, in addition to a compound of formula (I), one (or more) other active ingredient(s) useful in the treatment of the disorders and diseases indicated above.

Thus, the subject of the present invention is also pharmaceutical compositions containing a compound of formula (I) according to the present invention combined with one (or more) active ingredient(s) chosen from one of the following therapeutic classes:

-   -   another antagonist or allosteric modulators of the CB₁         cannabinoid receptors;     -   a modulator of the CB₂ cannabinoid receptors;     -   an antagonist of the AT₁ receptors for angiotensin II;     -   a converting enzyme inhibitor;     -   a calcium antagonist;     -   a diuretic;     -   a beta-blocker;     -   an antihyperlipemic or an antihypercholesterolemic;     -   an antidiabetic;     -   another anti-obesity agent or agent acting on metabolism         disorders;     -   a nicotine agonist, a partial nicotine agonist;     -   an antidepressant, an antipsychotic, an anxiolytic;     -   an anticancer agent or an antiproliferative agent;     -   an opioid antagonist;         as well as:     -   a memory enhancer;     -   an agent useful in the treatment of alcoholism or of withdrawal         symptoms;     -   an agent useful for treating osteoporosis;     -   a steroidal or non-steroidal anti-inflammatory agent;     -   an antiinfective;     -   an analgesic;     -   an antiasthmatic.

The expression antagonist of the AT₁ receptors for angiotensin II is understood to mean a compound such as candesartan cilexitil, eprosartan, irbesartan, losartan potassium, olmesartan medoxomil, telmisartan, valsartan, it being possible for each of these compounds themselves to be combined with a diuretic such as hydrochlorothiazide.

The expression converting enzyme inhibitor is understood to mean a compound such as alacepril, benazepril, captopril, cilazapril, enalapril, enalaprilat, fosinopril, imidapril, lisinopril, moexipril, perindopril, quinapril, ramipril, spirapril, temocapril, trandolapril, zofenopril, it being possible for each of these compounds themselves to be combined with a diuretic such as hydrochlorothiazide or indapamide or with a calcium antagonist such as amlodipine, diltiazem, felodipine or verapamil.

The expression calcium antagonist is understood to mean a compound such as amlodipine, aranidipine, benidipine, bepridil, cilnidipine, diltiazem, efonidipine hydrochloride ethanol, fasudil, felodipine, isradipine, lacidipine, lercanidipine hydrochloride, manidipine, mibefradil hydrochloride, nicardipine, nifedipine, nilvadipine, nimodipine, nisoldipine, nitrendipine, terodiline, verapamil.

The expression beta-blocker is understood to mean a compound such as acebutolol, alprenolol, amosulalol, arotinolol, atenolol, befunolol, betaxolol, bevantolol, bisoprolol, bopindolol, bucumolol, bufetolol, bunitrolol, butofilolol, carazolol, carteolol, carvedilol, cloranolol, epanolol, esmolol, indenolol, labetalol, landiolol, levobunolol, levomoprolol, mepindolol, metipranolol, metoprolol, nadolol, nebivolol, nifenalol, nipradilol, oxprenolol, penbutolol, pindolol, propranolol, salmeterol, sotalol, talinolol, tertatolol, tilisolol, timolol, xamoterol, xibenolol.

The expression antihyperlipemic or antihypercholesterolemic is understood to mean a compound chosen from fibrates such as alufibrate, beclobrate, bezafibrate, ciprofibrate, clinofibrate, clofibrate, etofibrate, fenofibrate; statins (HMG-CoA reductase inhibitors), such as atorvastatin, fluvastatin sodium, lovastatin, pravastatin, rosuvastatin, simvastatin, or a compound such as acipimox, aluminium nicotinate, azacosterol, cholestyramine, dextrothyroxine, meglutol, niceritrol, nicoclonate, nicotinic acid, beta-sitosterol, tiadenol.

The expression antidiabetic is understood to mean a compound belonging to one of the following classes: sulphonylureas, biguanidines, alpha glucosidase inhibitors, thiazolidinediones, metiglinides, such as acarbose, acetohexamide, carbutamide, chlorpropamide, glibenclamide, glibornuride, gliclazide, glimepiride, glipizide, gliquidone, glisoxepide, glybuzole, glymidine, metahexamide, metformin, miglitol, nateglinide, pioglitazone, repaglinide, rosiglitazone, tolazamide, tolbutamide, troglitazone, voglibose, as well as insulin and insulin analogues.

The expression another anti-obesity agent or agent acting on metabolism disorders is understood to mean a compound such as amfepramone, benfluorex, benzphetamine, indanorex, mazindole, mefenorex, methamphetamine, D-norpseudoephedrine, sibutramine, a topiramate, a lipase inhibitor (orlistat cetilistat), a PPAR agonist (Peroxisome Proliferator Activated Receptor Agonist), a dopamine agonist, a leptin receptor agonist, a serotonin reuptake inhibitor, a beta-3 agonist, a CCK-A agonist, an NPY inhibitor, an agonist of the MC 4 (melanocortin 4) receptors, an antagonist of the MCH (Melanin Concentrating Hormone) receptors, an orexin antagonist, a phosphodiesterase inhibitor, an 11β-HSD (11-β-hydroxysteroid deshydrogenase) inhibitor, a DPP-IV (dipeptidyl peptidase IV) inhibitor, an antagonist (or inverse agonist) of histamine H3, a CNTF (Ciliary Neurotrophic Factor) derivative, an agonist of the GHS (Growth Hormone Secretagogue) receptors, a ghrelin modulator, a diacyglycerol acyltransferase (DGAT) inhibitor, a phosphodiesterase (PDE) inhibitor, a thyroid hormone agonist, an antagonist of the glucocorticoid receptors, a stearoyl-CoA-desaturase (SCD) inhibitor, a modulator of phosphate, glucose, fatty acid and dicarboxylate transporters, a 5HT₂ antagonist, a 5HT₆ antagonist, a bombesine agonist.

The expression opioid antagonist is understood to mean a compound such as naltrexone, naloxone ou nalmefene.

The expression agent useful in the treatment of alcoholism and withdrawal symptoms is understood to mean acamprosate, benzodiazepines, beta-blockers, clonidine, carbamazepine.

The expression agent useful for treating osteoporosis is understood to mean for example biphosphonates such as etidronate, clodronate, tiludronate, risedronate.

According to the present invention, it is also possible to combine other compounds having antihyperlipemic, antihypercholesterolemic, antidiabetic or anti-obesity properties. More particularly, it is possible to combine compounds belonging to one of the following classes: PTP 1 B (Protein Tyrosine Phosphase-1B) inhibitors, agonists of the VPAC 2 receptors, GLK modulators, retinoid modulators, glycogen phosphorylase (HGLPa) inhibitors, glucagon antagonists, glucose-6-phosphate inhibitors, pyruvate dehydrogenase kinase (PDK) activators, modulators of RXR, FXR, LXR, inhibitors of SGLT (Sodium Dependant Glucose Transporter), CETP (Cholesteryl ester Transfer Protein) inhibitors, squalene synthetase inhibitors, squalene epoxidase inhibitors, triglyceride synthesis inhibitors, inducers of LDL (Low Density Lipoprotein) receptors, IBAT inhibitors, FBPase (fructose-1,6-biphosphatase) inhibitors, CART (Cocaine-Amphetamine-Regulated Transcript) modulators, antagonists of the orexin receptors.

According to another aspect of the invention, the compound of formula (I), one of its pharmaceutically acceptable salts and the other associated active ingredient may be administered simultaneously, separately or spread out over time.

The expression “simultaneous use” is understood to mean the administration of the compounds of the composition according to the invention contained in the same pharmaceutical dosage form.

The expression “separate use” is understood to mean the administration, at the same time, of two compounds of the composition according to the invention, each contained in a separate pharmaceutical dosage form.

The expression “use spread out over time” is understood to mean the successive administration of the first compound of the composition of the invention, contained in a pharmaceutical dosage form, followed by the second compound of the composition according to the invention, contained in a separate pharmaceutical dosage form. In this case, the time lapse between the administration of the first compound of the composition according to the invention and the administration of the second compound of the same composition according to the invention generally does not exceed 24 hours.

In the pharmaceutical compositions of the present invention for oral, sublingual, subcutaneous, intramuscular, intravenous, topical, local, intratracheal, intranasal, transdermal or rectal administration, the active ingredient of formula (I) above, or its salt, may be administered in a unit form for administration, mixed with conventional pharmaceutical excipients, to animals and to human beings for the prophylaxis or treatment of the above disorders or diseases.

The appropriate unit forms for administration comprise the oral forms such as tablets, soft or hard gelatin capsules, powders, granules and oral solutions or suspensions, forms for sublingual, buccal, intratracheal, intraocular or intranasal administration or for administration by inhalation, forms for topical, transdermal, subcutaneous, intramuscular or intravenous administration, forms for rectal administration and implants. For topical application it is possible to use the compounds according to the invention in creams, gels, ointments or lotions.

By way of example, a unit form for administration of a compound according to the invention in tablet form may comprise the following components:

Compound according to the invention 50.0 mg Mannitol 223.75 mg Croscarmellose sodium 6.0 mg Maize starch 15.0 mg Hydroxypropylmethylcellulose 2.25 mg Magnesium stearate 3.0 mg

By the oral route, the dose of active ingredient administered per day may be up to 0.01 to 100 mg/kg, in single or divided doses, preferably 0.02 to 50 mg/kg.

There may be specific cases where higher or lower dosages are appropriate; such dosages do not depart from the scope of the invention. According to the customary practice, the dosage appropriate for each patient is determined by the doctor according to the mode of administration, the weight and the response of the said patient.

The present invention, according to another of its aspects, also relates to a method for treating the pathologies indicated above, which comprises the administration, to a patient, of an effective dose of a compound according to the invention, or of one of its pharmaceutically acceptable salts. 

1. A Compound of formula (I):

in which: A represents a (C₁-C₆)alkylene group which is unsubstituted or substituted one or more times with a (C₁-C₃)alkyl group or a fluorine atom; R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more fluorine atoms; R₂ represents: either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being unsubstituted or substituted once or twice with a substituent each independently chosen from a fluorine atom, a group (C₁-C₄)alkoxyl, (C₁-C₄)alkyl, trifluoromethyl, —OCF₃, —CH₂OH, —CONH₂ or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group or a trifluoromethoxyl group; or an amino(C₁-C₆)alkyl group which is unsubstituted or substituted with one or several substituents each independently chosen from a fluorine atom, a hydroxyl group, a —CONH₂ group or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group or a trifluoromethoxyl group; or R₁ and R₂ together with the nitrogen atom to which they are attached constitute: either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the said radicals being unsubstituted or substituted with a phenyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl, —COR₁₁, or —CH₂COR₁₁ group; the phenyl group being itself unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being unsubstituted or substituted once or twice with a substituent each independently chosen from: a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃, —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; or —SO₂ NR₁₂R₁₃; or a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom or a hydroxyl, or a phenyl or pyridinyl group; the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a benzyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl, hydroxyl, trifluoromethyl or —OCF₃ group; or an aminophenyl or aminobenzyl group, the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or an amino(C₃-C₇)cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl or cyano group, the said (C₁-C₄)alkyl group being unsubstituted or substituted once or several times with a fluorine atom; R₃, R₄, R₅, R₆, R₇, R₈ each independently represent a hydrogen atom, a halogen atom, a —CN, —S(O)_(n)R₁₄ or —OS(O)_(n)R₁₄ group, or a (C₁-C₆)alkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, an —OH, —OR₁₄, —S(O)_(n)R₁₄, —OSO₂R₁₄ or —NHSO₂R₁₄ group, or a (C₁-C₆)alkoxyl group, which is unsubstituted or substituted with one or more substituents each independently chosen from a fluorine atom, an —OH, —OR₁₄, —S(O)_(n)R₁₄, —OSO₂R₁₄ or —NHSO₂R₁₄ group; R₉ represents an —OR₁₂, —CN, —CO₂H, NR₁₂R₁₃, —CONR₁₂R₁₃, —NR₁₅COR₁₂, —CONHNH₂, —CONHOH, —CONHSO₂R₁₄, —S(O)_(n)R₁₄, —SO₂NR₁₂R₁₃, —NR₁₈SO₂R₁₄ or —NR₁₅SO₂NR₁₂R₁₃ group, or an aromatic heterocycle chosen from:

R₁₀ represents a hydrogen or a (C₁-C₄)alkyl group; R₁₁ represents: a (C₁-C₄)alkyl, phenyl, benzyl, (C₁-C₄)alkoxyl, or (C₁-C₃)alkylene-O—(C₁-C₃)alkyl group, the said groups being unsubstituted or substituted with one or more substituents each independently chosen from a (C₁-C₄)alkoxyl group, a hydroxyl group or one or more fluorine atoms; a trifluoromethyl; or an NR₁₆R₁₇ group; R₁₂ and R₁₃ each independently represent a hydrogen atom or a (C₁-C₆)alkyl group optionally substituted with one or more substituents each independently chosen from a halogen atom, a (C₃-C₇)cycloalkyl, cyano, —OH or —OR₁₄ group; or R₁₂ and R₁₃ together with the nitrogen atom to which they are attached constitute a 4- to 7-membered heterocyclic radical which may contain a second heteroatom chosen from a nitrogen, oxygen or sulphur atom; n represents 0, 1 or 2; R₁₄ represents a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more fluorine atoms; R₁₅ represents a hydrogen atom or a (C₁-C₄)alkyl group; R₁₆ and R₁₇ each independently represent: a hydrogen atom; or a benzyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a (C₁-C₆)alkyl group which is optionally substituted with one or more halogen atoms, —OH, or —OR₁₄ groups; R₁₈ represents a hydrogen atom or a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more fluorine atoms; or its salt.
 2. The compound according to claim 1 of formula (I) in which: R₁ represents a hydrogen atom or a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more fluorine atoms; R₂ represents: either a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the radicals being substituted once or twice with a substituent each independently chosen from a fluorine atom, a group (C₁-C₄)alkoxyl, (C₁-C₄)alkyl, trifluoromethyl, —OCF₃, —CH₂OH, —CONH₂ or a phenyl group, the phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group or a trifluoromethoxyl group; or an amino(C₁-C₆)alkyl group which is substituted with one or several substituents each independently chosen from a fluorine atom, a hydroxyl group, a —CONH₂ group or a phenyl group, the said phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group or a trifluoromethoxyl group; the other substituents being as defined for the compounds of formula (I); or its salt.
 3. The compound according to claim 2 of formula (I) in which the radical R₂ represents a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the radicals being substituted once or twice with a substituent each independently chosen from a fluorine atom, a (C₁-C₄)alkoxyl, trifluoromethyl, —OCF₃, —CH₂OH or —CONH₂ group or a phenyl group, the phenyl group being unsubstituted or substituted once or twice with a substituent each independently chosen from a halogen atom, a —CF₃ group, a methoxyl group or a trifluoromethoxyl group; or its salt.
 4. The compound according to claim 1 of formula (I) in which: R₁ and R₂ together with the nitrogen atom to which they are attached constitute: either a piperazin-1-yl or 1,4-diazepan-1-yl radical, the radicals being substituted with a phenyl, benzodioxolyl, benzodioxolylmethyl, tetrahydrofuranylcarbonyl, —COR₁₁, or —CH₂COR₁₁ group; the phenyl group being itself substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radicals being substituted once or twice with a substituent each independently chosen from: a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃, —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; or —SO₂ NR₁₂R₁₃; or a (C₁-C₄)alkyl group which is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom or a hydroxyl, or a phenyl or pyridinyl group; the said phenyl or pyridinyl groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a benzyl group which is substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, wherein the piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl, hydroxyl, trifluoromethyl or —OCF₃ group; or an aminophenyl or aminobenzyl group, the aminophenyl or aminobenzyl groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a methyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or an amino(C₃-C₇)cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl or cyano group, the said (C₁-C₄)alkyl group being unsubstituted or substituted once or several times with a fluorine atom; the other substituents being as defined for the compounds of formula (I); or its salt.
 5. The compound according to claim 1 of formula (IB) in which: R₁ and R₂ together with the nitrogen atom to which they are attached constitute a homopiperidin-1-yl, piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl radical, the said radical being substituted once or twice with a substituent each independently chosen from: a fluorine atom, a cyano, —COR₁₁, —CONR₁₂R₁₃, —NR₁₂R₁₃, —NHCOR₁₄, —CH₂COR₁₁, —SO₂R₁₄ group; or —SO₂NR₁₂R₁₃; or a (C₁-C₄)alkyl group, wherein said (C₁-C₄)alkyl group is unsubstituted or substituted with one or more substituents each independently chosen from a halogen atom or a hydroxyl, or a phenyl or pyridinyl group; the said groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or a benzyl group which is substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl and cyano group; or a piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl group, wherein the piperidin-1-yl, pyrrolidin-1-yl or azetidin-1-yl groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a fluorine atom, a (C₁-C₄)alkyl, (C₁-C₄)alkoxyl, hydroxyl, trifluoromethyl or —OCF₃ group; or an aminophenyl or aminobenzyl group, the aminophenyl or aminobenzyl groups being unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a (C₁-C₄)alkyl, trifluoromethyl, hydroxyl, (C₁-C₄)alkoxyl or cyano group; or an amino(C₃-C₇)cycloalkyl group which is unsubstituted or substituted once or several times with a substituent each independently chosen from a halogen atom, a hydroxyl, (C₁-C₄)alkyl, (C₁-C₄)alkoxyl or cyano group, the said (C₁-C₄)alkyl group being unsubstituted or substituted once or several times with a fluorine atom; the other substituents being as defined for the compounds of formula (I); or its salt.
 6. The compound according to claim 1 in which A represents an unsubstituted (C₁-C₅)alkylene group and R₉ represents an —OR₁₂, —NR₁₂R₁₃, —CONR₁₂R₁₃, —NR₁₅COR₁₂, —CONHNH₂, —CONHOH, —S(O)_(n)R₁₄, —SO₂NR₁₂R₁₃, —NR₁₈SO₂R₁₄, or —NR₁₅SO₂NR₁₂R₁₃ group; or its salt.
 7. The compound according to claim 1, characterized in that the compound is chosen from the group consisting of: 1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; 1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(2-hydroxyethyl)-1H-pyrrol-3-yl]carbonyl}-4-phenylpiperidine-4-carboxamide; 1′-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(4-hydroxybutyl)-1H-pyrrol-3-yl]carbonyl}-4,4-difluoro-1,4′-bipiperidine-4′-carboxamide; and 4-(4-chlorophenyl)-1-{[1-(4-chlorophenyl)-5-(2,4-dichlorophenyl)-2-(3-hydroxy propyl)-1H-pyrrol-3-yl]carbonyl}piperidine-4-carboxamide; and their salts.
 9. A compound of formula (IIter):

in which: X represents a halogen atom, a hydroxyl, (C₁-C₄)alkoxyl or benzyloxy group; and A, R₃, R₄, R₅, R₆, R₇, R₈ and R₁₀ are as defined for the compounds of formula (I) according to claim
 1. 10. A process to prepare compound of formula (I) using the compound of claim
 9. 11. A Medicament, characterized in that it comprises a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof.
 12. A Pharmaceutical composition, characterized in that it comprises a compound of formula (I) according to claim 1 or a pharmaceutically acceptable salt thereof and at least one pharmaceutically acceptable excipient.
 13. A method of treating or preventing psychiatric disorders, of dependence on and withdrawal from a substance, cognitive disorders, attention and vigilance disorders, acute and chronic neurodegenerative diseases by administering compound of claim 1 to person in need thereof.
 14. A method of treating or preventing metabolism disorders, appetite disorders, craving disorders, obesity, bulimia, diabetes, metabolic syndrome or dyslipidemia by administering compound of claim 1 to person in need thereof.
 15. A method of treating or preventing pain, neuropathic pain, acute peripheral pain, chronic pain of inflammatory origin or pain induced by an anticancer treatment by administering compound of claim 1 to person in need thereof.
 16. A method of treating or preventing gastrointestinal disorders, emesis, diarrheal disorders, ulcers, or liver diseases by administering compound of claim 1 to person in need thereof.
 17. A method of treating or preventing inflammatory phenomena, immune system diseases, rheumatoid arthritis, diseases causing demyelinization, multiple sclerosis, bone diseases and osteoporosis by administering compound of claim 1 to person in need thereof.
 18. A method of treating or preventing motion diseases and disorders, in particular dyskinesia or Parkinson's disease, senile dementia and Alzheimer's disease by administering compound of claim 1 to person in need thereof. 